Saturday, May 18, 2024
5/18/2024
PROJECT SUMMARY Invasive aspergillosis is one of the most common fungal infections in immunocompromised patients. With the increasing number of susceptible patients and the threat of antifungal-resistance, the development of host- centric interventions is of paramount importance. Complement, a potent component of the innate immune system, is protective against many infections. On the other hand, complement overactivation has been shown to drive lung injury and inflammation. Pulmonary hemorrhage is a characteristic feature of invasive aspergillosis, and the interactions between pulmonary hemorrhage and complement activation are poorly understood. Intervening in the interactions between hemorrhage and complement may prove beneficial as a novel therapeutic intervention to manage pulmonary aspergillosis, and a number of complement inhibitors are either FDA- approved or in late-phase development. The overarching hypothesis in this project is that pulmonary hemorrhage in invasive aspergillosis leads to complement overactivation, leading to tissue injury and further hemorrhage. The dynamics of complement activation are complex and span multiple sites, making it difficult to predict how and when to intervene. We propose that mathematical modeling-based design of effective therapies in pulmonary aspergillosis can help in the discovery phase of understanding mechanisms of complement-mediated injury in pulmonary aspergillosis, and possible interventions of such mechanisms. As such we will leverage the power of mathematical modeling, closely coupled with in vivo models of pulmonary aspergillosis, to unravel the interactions of hemorrhage and complement in the lung and to systematically interrogate the model to determine possible points of intervention. In Aim 1, we will mechanistically explore the effects of the terminal component of the complement cascade in pulmonary aspergillosis. In Aim 2, we will build a multiscale mathematical model of pulmonary aspergillosis to capture the mechanisms that connect hemorrhage and complement activity, validating these mechanisms in vivo. We will then use the model to derive a prioritized set of interventions that will be validated in mouse models of pulmonary aspergillosis. This research is intended to train a PhD mathematician with a background in mathematical modeling in experimental biology and facilitate his transition to an independent investigator. He will be mentored by a physician-scientist with expertise in lung host defense and a complement biologist and overseen by an advisory committee composed of experts in computational modeling, lung biology, and mycology. This training will be enhanced by the rich scientific environment at the University of Florida, together with rigorous coursework in advanced immunology, mycology, and microbiology, and training in grant writing and scientific rigor. Taken together, this project will train a transdisciplinary scientist for an independent investigative career.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
